Excitatory amino acids (EAA) have recently emerged as a new class of neurotransmitters involved in the control of a wide variety of neurophysiological and neuroendocrinological phenomena. In addition to these actions, EAA are considered as excitotoxins, in view of their ability to induce neuronal death as the result of neuronal hyperstimulation. Gamma-amino-butyric acid (GABA) is the prototype neurotransmitter of the classical inhibitory amino acid system, whereas glutamic acid (GLU) is considered as the major representative of the excitatory amino acid neurotransmitters. Studies were conducted to analyze possible interactions between excitatory and inhibitory amino acids in the mechanism controlling neuropeptide secretion. We have used GABA agonists and antagonists as tools to evaluate the participation of the inhibitory amino acid neurotransmission on GLU-induced LHRH release from arcuate nucleus-median eminence fragments incubated in vitro. GABA-A receptors appear to participate in GLU-evoked LHRH secretion, since bicuculline, GABA-A receptor antagonist, blocked the stimulatory effects of GLU on LHRH release. Interestingly, GLU-induced LHRH secretion was enhanced by activation of GABA-A receptors by muscimol, a GABA-A receptor agonist, in an additive manner. In contrast, GABA-B receptors seem to negatively modulate the effects of GLU. Baclofen, a GABA-B receptor agonist, blocked GLU-evoked LHRH secretion. This effect was abolished by the GABA-B receptor antagonist phaclofen. In summary, our data clearly indicate that a cross-talk between the excitatory and inhibitory amino acid systems constitutes a physiologically important interactive mode in the regulatory mechanisms controlling LHRH secretion and, thereby, reproductive functions.